Abstract 6184: Kras Co-mutations lead to resistance to mutant TP53 targeted therapy in mouse models of spontaneous non-small cell lung cancer
Authors: David T. Costa, Shaylyn Grier, Melanie Perez, Li Gao, Miguel A. Villalona-Calero, Wenrui Duan
Journal: Cancer Research (2022)

Abstract Background: Lung cancer results in more than 131,000 deaths per year with estimated 236,000 new cases in 2021 in the United States. About 85% of lung cancers are non-small cell lung cancer (NSCLC). TP53 is an important tumor-suppressor and about 50% of human lung NSCLCs contain a mutant TP53. Targeting of mutant p53 is very limited due to the lack of drugs. PRIMA-1 is a first in class anti-mutant TP53 molecule with the ability to induce apoptosis by restoring the wild-type function of TP53 through covalently binding and modifying thiol groups in the central domain of the mutated protein. Recently, the FDA granted breakthrough therapy designation to the PRIMA-1 methylated analog, APR-246 in combination with azacytidine for the treatment of patients with myelodysplastic syndromes and a TP53 mutation. The major setback of targeted therapy today continues to be resistance. Herein, we report our findings related to resistance to PRIMA-1 targeted therapy in spontaneous P53 mutant driven NSCLC. Methods: We have previously reported the generation of a line of transgenic mice with a human mutant p53(273H) expressed in a lung-specific manner. Human mutant TP53 expression was regulated under the transcriptional control of the human surfactant protein C (SP-C) promoter. After the age of 12 months, the mice developed spontaneous lung adenocarcinomas. We treated SPC-p53-273H lung tumor mice via intraperitoneal injection (i.p) with PRIMA-1 at a dose of 100 mg/kg in 0.2 mL PBS every other day for two weeks. The tumors were identified using micro-computed tomography (micro-CT) system and pre-and post-treatment diameters were estimated based on the CT image. K-ras status was analyzed by PCR-based Sanger sequencing. Results: Of the 10 lung tumor-bearing mice treated with PRIMA-1, micro-CT derived sum of the largest diameters indicated that six mice (60%) experienced tumor volume reductions whereas four mice experienced tumor volume increase. Sequencing analysis showed five tumors contained K-ras mutations (two p.G12D, one p.G12F, one p.G12V and one p.Q61L). On average, lung tumor diameter had a 31% reduction post-treatment of PRIMA-1 for the lung tumors containing wild-type K-ras gene. Whereas it increased 18% on the average post-treatment of PRIMA-1 for the lung tumors containing a mutant K-ras gene. There is a significant difference statistically (p = 0.016) in the response to the treatment of PRIMA-1 between the mutant K-ras cohort and the wild-type K-ras cohort. Conclusion: PRIMA 1 therapy results in antitumor activity against P53 mutant lung tumors. However, the presence of K-ras co-mutation is a significant resistance factor. Combination of APR-246 and K-ras inhibitor therapy would be needed to overcome this resistance. Citation Format: David T. Costa, Shaylyn Grier, Melanie Perez, Li Gao, Miguel A. Villalona-Calero, Wenrui Duan. Kras Co-mutations lead to resistance to mutant TP53 targeted therapy in mouse models of spontaneous non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6184.